Numerous in vitro and in vivo studies have shown there are bacteria that may promote oral health. Many of these bacteria have the ability to use the amino acid arginine to raise dental plaque pH, thus inhibiting the formation of cavities. Additionally, many of these potentially beneficial bacteria are able to interfere with the growth o oral pathogens, like Streptococcus mutans, and to block the ability of S. mutans to produce antibiotics that kill beneficial organisms. Thus, identifying isolates of these bacteria with poten beneficial properties and understanding how they modulate disease development would be tremendously valuable in controlling oral infectious diseases, like dental caries and periodontitis The work proposed here is built on the foundation that individual isolates display a profound spectrum of anti-cariogenic properties: in their capacity to utilize arginine via the arginine deiminase system; in their capacity to exert strong antagonistic effects on the growth of oral pathogens; and in their abilities to interfere with the deployment of antagonistic molecules by oral pathogens. When implemented, the study will yield a much-needed, thorough understanding of the genomic structure and associated phenotypic behaviors of a group of abundant commensal streptococci, along with the mechanisms by which these organisms exert probiotic effects in in vitro, in an animal model, and in the human oral cavity. To accomplish these goals, Aim 1 conducts a comparative and functional genomic analysis of a discrete group of low-passage, clinical isolates to characterize the mechanisms for their enhanced capacity to moderate pH through arginine metabolism, to dissect the diverse repertoire of strategies they employ to antagonize oral pathogens, to understand the genetic basis for the ability of these isolates to resist antagonistic molecules deployed by oral pathogens, and to identify genetic markers associated with isolates that have particularly beneficial properties. In Aim 2, we will establish a mouse model of dental caries that is suitable for evaluating the capacity of, and the mechanisms by which, selected isolates from Aim 1 are able to inhibit establishment, persistence, and the initiation and progression of dental caries by S. mutans. Aim 3 will contrast gene expression patterns in isolated human dental plaque from caries-active and caries-free subjects to understand how arginine metabolic pathways and the weapons of commensals and pathogens are deployed in health and disease, as well as to identify novel genetic biomarkers for health and disease. Collectively, the study will provide a comprehensive understanding of mechanisms of pro- and pre-biotic for control of dental caries and guide the development of effective probiotics and symbiotic, while providing the added benefit of enhancing the quality of oral health risk assessments.